(cid:38)(cid:68)(cid:83)(cid:86)(cid:88)(cid:74)(cid:72)(cid:79)(cid:3)(cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87)(cid:3)(cid:20)(cid:19)(cid:19)(cid:25)
`
`Page 1 of 8
`
`

`

`1
`PHARMACEUTICAL FORMULATIONS
`
`5,738,871
`
`2
`
`This application is a division, of application Ser. No.
`08942078, filed May 13. 1994 now 11.8. Pat. No. 5,532.
`002.
`This invention relates to the formulation of fat—soluble
`nutrients.
`Fat-soluble nnnients include mono-. di- or tri-glyoerides
`having at least one mono- or poly—unsaturated fatty acid
`chain. as well as the fat-soluble vitamins A. D, E and K.
`Certain of the fat—soluble glyceride nutrients are often
`referred to as essential fatty acids (EFAs), although more
`properly they should perhaps be called glycerides of essen-
`tial fatty acids.
`Fat-soluble nutrients including glycerides and vitamins
`are susceptible to malabsorption. In the extreme. there are
`conditions associated with malabsorption. particularly of
`EFAS, such as cystic fibrosis. chronic pancreatitis, biliary
`atresia, muscular dystrophy. multiple sclerosis and food
`allergies. These conditions have been linked with deficien—
`cies of one or more of the fat-soluble nutrients.
`As for the vitamins. vitamin A is necessary for growth
`and differentiation of epithelial tissue and is required for
`grth of bone. reproduction and embryonic development.
`It has an essential role to play in the function of the retina:
`vitamin A deficiency interferes with vision in dim light. a
`condition known as night blindness.
`Vitamin D deficiency results in rickets. The vitamin D
`group of compounds regulates calcium absorption by the
`small intestine and calcium metabolism in bone.
`It is not entirely clear what is the elfect of deficiency of
`vitamin E. However. this vitamin may be important for its
`properties as a potent anti-oxidant. Furthermore. it appears
`to be important in maintaining the integrity and stability of
`biological membranes as well as being important in con-
`trolling prostaglandin synthesis.
`Vitamin K is a dietary substance which is essential for the
`normal biosynthesis of several factors required for clotting
`of blood.
`From the above. it is clear that it is essential that the
`
`individual both ingest and absorb adequate quantities of
`fat-soluble nutrients. be they essential fatty acid glycerides
`or fat-soluble vitamins. The absorption of fat—soluble nutri—
`ents is dependent on the individual’s capacity to digest and
`absorb fat. which is generally achieved physiologically
`through the lymphatic system. This is well established for
`fatty acid glycerides. and it has been demonstrated in
`humans that the lymphatic pathway is the major absorption
`pathway for vitamin E.
`Adequate pancreatic enzyme. bicarbonate and bile output
`are required for lymphatic absorption. If the diet is too low
`in fat. there may be inadequate secretion of emulsifying
`substances which may lead to poor fat-soluble nutrient
`absorption. Conversely. if the diet is excessively high in fat
`such that the gall—bladder and pancreatic system are over-
`loaded and unable to process all the fat. then absorption may
`be reduced It may be that the lymphatic system. or the
`earlier stages in the fat-absorption process that lead to the
`lymphatic system. of those individuals who have a defi—
`ciency in one or more far-soluble nutrients is defective in
`some way and so prevents proper absorption. If this is
`correct. it explains why the conventional administration of
`excess additional quantifies of the nutrient in question will
`not solve the problem
`Even in those individuals without impaired lymphatic fat
`absorption capabilities. the eficiency of absorption of. for
`example. vitamin E is relatively poor. being about 20 to
`
`1'0
`
`15
`
`25
`
`30
`
`35
`
`45
`
`55
`
`Page 2 of 8
`
`40%. and so there is a general need to be able to improve
`absorption of fat—soluble nutrients.
`The body does have an alternative absorption route
`through the portal system. This pathway applies to water-
`soluble substances and to poorly water-soluble substances
`which have been solubilised. for example by non-ionic
`surfactants. It has been demonstrated that vitamin E is better
`absorbed from orally administered aqueous solutions than
`from oily solutions. and that vitamin E in aqueous solution
`is absorbed by patients suffering from fat-malabsorption
`diseases-
`Capitalising on this alternative ptrtal route. aqueous
`solutions containing micellised vitamin preparations have
`been available for many years. US. Pat. No. 4572915. for
`example. relates to clear micellised solutions of fat-soluble
`essential nutrients. Unfornrnately, aqueous micellised prepa~
`rations can have a number of drawbacks. such as stability,
`taste. smell and inconvenience. all of which are factors
`which make patient compliance dill'icult.
`GB-A—2145331 discloses various surfactant-containing
`compositions of vitamins A and E in soft elastic gelatin
`capsules. The surfactant used is polysorbate 80. which is a
`common name for a polyoxyethylene sorbitaa ester surfac—
`tant. Certain of the formulations exemplified lead to the
`production of unstable emulsions. when they are mixed with
`water.
`
`Although capsules are a highly suitable means of admin-
`istration of fat—soluble nutrients. it would be preferable to
`use hard gelatin capsules rather than soft gelatin capsules.
`This is because hard gelatin capsules have more consumer
`appeal. and because there is a more open supply market for
`hard gelatin capsules. However, there is a problem: liquid
`formulations of a fat-soluble nutrient and a nonionic surfac-
`tant tend to cause emtn'ittlement of hard gelatin capsules.
`and so lead to unacceptably poor stability characteristics of
`hard gelatin capsules filled with such formulations. It is to
`providing a solution to this problem that the present inven-
`tion is addressed.
`It has been found that a gelatin softening agent. such as
`may conventionally be used in the manufacture of soft
`gelatin capsules. can.
`if incorporated into the capsule
`contents. significantly reduce embrittlement. Possibly this is
`because the softening agent can leach into the gelatin shell
`at a sufl'icient rate and in a sufiicient amount to prevent
`embrittlement. but this is only a suggestion for the basis of
`the observed eflicacy.
`According to a first aspect of the invention. there is
`provided a hard gelatin capsule containing: (a) a fat-soluble
`nutrient: (b) a nonionic surfactant; (c) a gelatin softening
`agent; and optionally (d) water.
`Hard gelatin capsules. sometimes also known as hard-
`sheil gelatin capsules. are well known. The shells are gen-
`erally supplied to the pharmaceutical fomurlator in mm
`interlocking U-sectioned shell portions. one of which is
`filled with the capsule contents and the other of which is
`placed over the filled shell portion to act as a cap. The two
`shell portions can then be sealed by any convenient means
`such as by gelatin banding. which is preferred. or by the
`LICAPS system marketed by the Capsugel division of Parke
`Davis. (The word LICAPS is a trade mark.) Hard gelatin
`capsule shells are available from the Elanco division of Eli
`Lilly. from the Capsugel division of Parke Davis and from
`runny other sources. They come in a variety of standard
`sizes. for example sizes “00”. “0”. "I". “2“ and “3".
`The term “fat—soluble nutrient" includes the fat-soluble
`vitamins and glycerides of fatty acids. that is to say mono-.
`di- or triglycerides optionally having at least one mono— or
`
`Page 2 of 8
`
`

`

`3
`
`5,738,871
`
`4
`
`10
`
`15
`
`poly-unsaturated fatty acid (which may be an essential fatty
`acid) chain. Essential fatty acid glycerides include glycer-
`ides of essential fatty acids. which may for example be from -
`CM to Cu with. for example. from 1 to '7. for example 2 to
`5. unsaturated bonds. There are two principal EFA series, the
`omega-3 and omega-6 series: the number denotes the num-
`ber of the first double bond from the methyl end of the
`hydrocarbon chain of the fatty acid residue in the glyceride.
`Linoleic acid is an omega-6 EPA and alpha~linolenic acid is
`an omega-3 EPA. The glycerides of oleic acid. which is a
`mono-unsaturated fatty acid, are other important fat-soluble
`nutrients.
`The omega-6 essential fatty acids are more prevalent in
`plant than animal food sources in western diets. Linoleic
`acid is found abundantly'in many warm weather vegetable
`seed oils. for example safilower, corn. soya bean and sun—
`flower oil. Gamma-linolenic acidIs found'in evening prim-
`rose oil (EPO). borage oil and oil of blackcurrant. The
`omega-3 EFAs are found predominantly in fish oils and to a
`smaller extent in cold weather seed oils such as flaxseed and
`linseed. The principal omega-3 EFAs are eicosapentacnoic
`acid (EPA) and docosahexaenoic acid (DHA). Vegetable oils
`may also include glycerides of saturated fatty acids includ«
`ing palmitic acid and stearic acid.
`Other esters of fatty acids are also within the term
`‘Tat-soluhle nutrient”. Examples include esters with lower
`(eg C1-C5) alcohols. such as ethyl esters.
`More than one fat-soluble nutrient may be present.
`Natural oils which are a mixture of fat-soluble nutrients
`may be used in capsules in accordance with the present
`invention. Example of suitable nahiral oils which can serve
`as fat-soluble nutrients include sweet almond oil. arachis oil.
`corn oil, cottonseed oil. grape seed oil. olive oil. saiflower
`oil, hybrid safllower oil (high oleic acid). sesame oil. soya-
`bean oil. sunflower oil and high oleic sunflower oil. Table 1
`shows typical compositions of the acids which are presented
`as glycerides in various natural oils.
`
`TABLE 1
`
`C1610
`C1320
`C1311
`C1812
`C1313
`
`Sweet Almond Oil
`6
`2
`1'0
`22
`Arachis Oil
`8
`3
`56
`26
`Corn Oil
`'?
`3
`43
`39
`Cottonseed Oil
`19
`2
`33
`39
`Grape Swd 0i]
`2
`T
`ill-25
`62—76
`max
`than
`max
`Olive Oil
`10
`2
`3i
`5
`Safllower Oil
`6
`2
`12
`78
`Hybrid Saflower Oil
`5
`31
`12
`(high Oleic Acid)
`Sesame Oil
`9
`45
`40
`Soybean 0i]
`9-16
`19-26
`50-57
`Sunflower 011
`5—11
`14—30
`55-74
`
`2
`l
`1
`
`5-9
`1man
`
`4
`1—2
`44?
`
`9
`30
`4
`4
`High Olelc Sunflower
`Oil
`
`55
`
`35
`
`45
`
`TABLE 2-continued
`
`
`C1670
`{318:0
`018:1
`(218:2
`(213:3 '
`(213:4
`
`
`—
`24
`37
`Borage Oil
`Blackcurrant
`6
`1
`11
`44
`33
`4
`Seed Oil
`
`
`Blackcurrant seed oil is of additional interest in that the
`(118:3 is made up of alpha-linolenic acid (for example, about
`15%) as well as the gamma-linoleum acid (for example
`about 18%). The latter is the principal component of the
`C183 of evening primrose oil and borage oil.
`Oils containing EFAs of the omega-3 family include fish
`oils. which can be refined to contain various levels of
`eicosapentaenoic acid (EPA) and docosahexaenoic acid
`(DI-IA). Examples would be:
`Average —12% EPA and 8% DHA
`Intermediate —-20% EPA and 10% DEA or
`High —-25% EPA and 12% DHA
`Sardine oil and salmon oil are examples of fish oils having
`high levels of EPA and DHA.
`Linseed oil is a source of alpha-linolenic acid.
`Fat—soluble vitamins include vitamins A. D. E and K.
`The term “vitaminA” as used in this specification not only
`includes Ictinol and its active esters. but also other cornn
`
`pounds that exhibit the biological properties of retinol.
`Carotene, or provitamin A. is a very potent source of retinol
`and is therefore regarded as being within the definition of
`“vitamin A” for the purpose of this specification.
`The two principal D vitamins are vitamin D2 (caldferol)
`and vitamin D3 (cholecalciferol). There appears to be no
`practical dilference between the two. The term “vitamin D“
`as used in this specification includes all active forms.
`The term “vitamin E” as used in this specification
`includes the group of chemically related compounds of
`which the most active is alpha—tooopherol. Naturally occtu—
`ring vitamin E has the d—configuration. as opposed to a
`mixture of synthetic alpha-woopberol which is designated as
`dl—alpha—tocopherol. ct—alpha—tocopherol can suffer from
`instability in some instances and it can then be replaced by
`the more stable d~alpha—tocopheryl acetate form. All com-
`pounds and derivatives having the biological activity of
`d-alpha-tocopherol are included within the term “vitamin
`E".
`Natural vitamin E is available as a by-product of veg-
`etable oil production. where it is extracted as the alcohol
`d-alpha—tocopherol. or as the synthesised acetate which is
`generally more stable than the alcohol “the natural (d—)
`forms are more active than the synthesised (dl-) form.
`Relative activities are
`
`
`1030 iutg
`dl-alpha-tocopheryl acetate
`1100 his
`dl-alptn-tooopheml
`1360 hits
`d—alpha-tooopheryl acetate
`
`d-aipha-looopheroi 1490 iutg
`
`Natural oils containing essential fatty acids of the
`omega-6 family include evening primrose oil, borage oil and
`blackcurrant seed oil. The percentage composition of the
`principal fatty acids in these oils is shown in Table 2.
`
`TABLE 2
`
`
`(315:0
`(118:0
`(313:1
`(218:2
`C1813
`(218:4
`
`
`Evening
`Prinu'oee 011
`
`6
`
`2
`
`IO
`
`72
`
`10
`
`—
`
`Page 3 of 8
`
`d-alpha-tocopherol is not normally available as a highly
`purified oil (generally up to 67% purity). whereas the others
`are generally available in greater purity in their common
`commercially available forms; for example. certain com-
`mercially available d—alpha—tocopheryl acetate is available at
`81% purity. and this is quite acceptable in practice.
`Vitamin K is a dietary substance which is essential for the
`normal biosynthesis of several factors required for clotting
`of blood. Vitamin K activity is associated with two natural
`
`65
`
`Page 3 of 8
`
`

`

`5,738,371
`
`5
`substances. vitamin K1 (phytenadione) and vitamin K2
`(methaquinone). Again. the term ‘yitamin K" as used in this
`specification covers all compounds having vitamin K activ-
`ity.
`The amount of fat-soluble nutrient present will depend
`upon its nature. For glycerides and mixtures of them and
`vitamin E. amounts of from 50 to 300 mg per capsule are
`preferred. with from 150 to 250 mg being typical. For
`vitamin A. amounts of from 5 to 150 mg per capsule are
`suitable, with from 10 to 50 mg being typical. For vitamin
`K. amounts of from 0.1 to 10 mg pa capsule. typically 0.5
`to 5 mg. may be present. For Vitamin D, much smaller
`amounts. such as from 0.001 to 0.1 mg. typically 0.005 to
`0.05 mg. may be present. Clearly. the amount present will
`also depend upon the size of capsule used. So. for example.
`up to 300 Lil. of vitamin E could be formulated in a single
`capsule by means of the present invention.
`Component (b) of a capsule in accordance with the first
`aspect of the invention comprises a nonionic surfactant
`Preferred nonionic surfactants are polyoxyethylated com-
`pounds. The degree of polyoxyethylation may range from
`about 15 to about 60. Apolyoxyethylation range of from 20
`or 30 to 45 is preferred. Slufactants preferred for use in this
`invention include polyexyethylated castor oil; and pelyoxy—
`ethylated hydrogenated caster oils. POE(40) hydrogenated
`caster oil is particularly suitable. Commercially available
`samples are sold under the trade mark CREMOPHOR RH40
`(from BASF) or CRODUREI‘ 40 from Croda. A suitable
`polyexyethylated castor oil is POE(35) castor oil. which is
`available commercially under the trade name CREMO-
`PHOR EL(fi-0m BASF) orETOCAS 35 (from Gods). It has
`generally been found that an unhydrogenated caster oil—
`derived surfactant is preferable for use when formulating
`vitamin E whereas a unhydrogenated caster oil, or a mixhue
`of hydrogenated and unhydrogenated caster oils. is prefer-
`able when preparing capsules containing glycerides of
`essential fatty acids and vitamins A. D and K. It will be
`appreciated that the surfactant. like the fat-soluble nutrient.
`may be present either as a single entity or as a mixurre.
`Polyexyethylated (optionally hydrogenated) caster oils
`are not the only surfactants 'which can be used in this
`invention. Other suitable poiyoxyethylated surfactants
`include polyoxyethylated glycol monoethers. pelyoxyethy-
`lated fatty acids and polyoxyethylated sorbitan fatty esters or
`polysorbates. such as those sold under the trade mark
`TW'BEN for example TWEEN 20 or TWEENT 80). Other
`nonionic surfactants are also useful. including sorbitan fatty
`acid esters. pelyoxamers, polyethylene glycol fatty acid
`esters and polyethoxylated glyceryl fatty acid esters and
`other polyeflroxylated polyaleohol fatty acid esters.
`Examples of such surfactants are the surfactants sold
`under the trade mark GEZLUCIRE and LABRAFIL by Gat-
`tefesse; these surfactants are the products of the alcoholysis
`reaction between triglyceride components of vegetable oils
`or fats and hydroxyl groups of polyslcehols. The lipophiles
`are saturated natural fats or oils and are essentially hydro-
`genated palm kernel and palm oil. The hydrophiles are
`polyoxyethyleneglycol polyalcohols with molecular weights
`between 300 and 1500.
`Certain surfactantloil combinations tend to give better
`results than others. as might be expected when working with
`a complex mixture of heterogeneous species. Nevertheless.
`it is quite within the capability of those skilled in the art to
`prepare adequate and even excellent formulations when
`working within the teaching of this specification and using
`no more than routine experimentation.
`Nonionic surfactants preferred for use in this invention
`have a hydrophile-lipoPhile balance {HLB} value of at least
`
`1.0
`
`15
`
`25
`
`35
`
`45
`
`50
`
`55
`
`6
`10. For example. POE (20) sorbitan u‘istearate. sold under
`the trade mark'IWEEN 65, is suitable and has an HLB value
`of 10.5. In many instances. however. an BLB value of at
`least 12 will be preferred: POE (35) castor oil has an HLB
`value of 12.5 and POE (40) hydrogenated castor oil has an
`HLB of 13.0.
`Whatever the precise chemical structure of the surfactant
`or surfactants used. it is generally preferred to use one or
`more of those that have been already cleared for human
`ingestion. Therefore. surfactants with a low toxicity are
`preferred. For example. surfactants having an LDSO exceed—
`ing 10 glltg and preferably 15 glitg. are generally suitable.
`The absence of other side effects is of course also appro-
`priate. Although surfactants which have already been
`approved for human ingestion are naturally preferred. the
`use of other surfactants is not ruled out. not least because
`they may in time come to be approved for human ingestion.
`The surfactant can be present in any suitable amount. for
`example from 30% (wlw) to 99% (wlw). based on the total
`weight of the formulation used for filling the capsules. For
`example, surfactant levels may range from 50 to 500 mg per
`capsule. with 200—460 mg being typical in some cases,
`although the amounts may be lower or even higher. In cases
`of small quantities of active (eg vitamins A. D. K) it is not
`actually necessary to have so much surfactant. but it is left
`in for convenience in filling and so as to not have so much
`dead space in the capsule. It is difficult to fill capsules
`smaller than size “2" hard gelatin capsules. but small cap-
`sules may sometimes be appropriate.
`The ratio of surfactantzfat-soluble nutrient will generally
`be atleast 1:1.Aratie offrom 1:1 or 1.25:1 to 1.75:1 or 2:1
`will be typical. and ratios of from [0:1 to 1.5:! will often
`be used in practice. The ratios applied to vitamins A. D and
`K tend to be very high for surfactantzactive (10:1. 33000:1.
`and 330:1 respectively). but these high ratios are not in fact
`anywhere near necessary.
`Component (c) is a gelatin softening agent. The gelatin
`softening agent can be any compatible material that func-
`tions appropriately. Generally, suitable materials can be
`found by reference to the art of manufacturing soft gelatin
`capsules. where such materials are incorporated into the mix
`that goes to form the gelatin wall itself. Particularly suitable
`gelatin softening agents are glycerol. propylene glycol and
`glyceryl mono-oleate. Sorbitol may also be suitable.
`Glyceryl mono-eleaie has a further advantage in that it
`can enhance the stability of the mixture used to fill the hard
`gelatin capsules. This can be useful if the particular com-
`bination of ingredients used would otherwise have a ten-
`dency to result in phase separation. For example. a mixture
`of CREMOPHOR R1140 POE (40) hydrogenated caster oil
`and various oils (such as evening primr05e oil. fish oil.
`borage oil or blackcurrant seed oil) may under certain
`conditions separate into two phase; this can be counteracted
`by the addition of glyceryl mono—oleate.
`Although any of the gelatin softening agents (particularly
`those preferred agents discussed above) may be found to be
`highly effective when used individually. there appears to be
`a father benefit to be had when glyceryl menooleate is used
`in conjunction with another gelatin softening agent. such as
`glycerol or propylene glycol. This further benefit
`is an
`enhancement of the gelatin softening action.
`The amount of gelatin softening agent used will generally
`be selected adequately to prevent embrilflernent of the
`capsule. but lnsuificient to cause ready deformability of the
`capsule. Regard should be had to the fact that hard gelatin
`capsules are often sold in blister packs. and so the capsule
`shells should be tough enough to withstand being pushed
`
`Page 4 of 8
`
`Page 4 of 8
`
`

`

`5,738,871
`
`7
`out: of such packs without unacceptable deformation. In
`general terms the gelatin softening agent should for prefer—
`ence be present in an amount up to 10% (WW) based on the
`weight of the non-oil components. for example from 3% to
`6%. unless the agent comprises glyceryl mono-oleate. in
`which case the glyceryl mono-cleats: can be present in an
`amount up to 30% (why). on the same basis. for example
`from 3% or 5% to 20% or 25%.
`Water may be present in formulations in accordance with
`the invention. Its presence is not necessarily obligatory. but
`in some instances added or inherent water may be found to
`be advantageous. For example. mixtures of particular pro—
`portions of certain surfactants and gelatin softening agents
`(such as a mixture of CREMOPHOR R1140 POE (40 )
`hydrogenated castor oil and 4% glycerol) are virtually
`opaque at room temperature and may paradmrically be
`clarified by the addition of water. Water may be added up to
`an amount of 5 or 6% (whv) based on the weight of the non
`oil components. for example fromz to 4%. Even if it is not
`specifically added. water may be provided when the surfac-
`tant is added as certain surfactants are hygroscopic.
`The fat-soluble nutrientls). the surfactant(s) or PEG(s).
`the gelatin softening agent and optionally the water may be
`the only ingredients in the capsule contents. It is not nec-
`essary for any further ingredient to be present. but under
`some circumstances additional materials may be present.
`One particular extra ingredient that may be suitable in some
`circumstances is an antioxidant; the precise type of antioxi-
`dant will depend upon the type of oil being used. It is also
`possible. but not necessary. to incorporate extra excipienls if
`desired.
`Generally liquid formulations comprising the contents of
`hard gelatin capsules in accordance with the first aspect of
`the invention themselves form a second aspect of the inven-
`tion.
`Therefore, according to a second aspect of the invention.
`there is provided a formulation comprising (a) a fat—soluble
`nutrient; (b) a nonionic surfactant; (c) a gelatin softening
`agent; and optionally ((1) water.
`According to a third aspect of the invention. hard gelatin
`capsules in accordance with the first aspect of the invention
`described above can simply be prepared by at least partially
`filling hard gelatin capsule shells with a formulation of the
`second aspect. If desired. the components may be heated
`(say to about 60° C.) and then cooled (say to 40° C.) before
`encapsulation. Conventional filling and. if required. sealing
`techniques may be used. although the use of such techniques
`which are themselves innovative is not of course precluded.
`According to a fifth aspect of the invention.
`there is
`provided a process for preparing a formulation in accor-
`dance With the second aspect.
`the process comprising
`admixing the ingredients together.
`Preferred features of the second to fifth aspects of the
`invention are as for the first aspect. mutatis mutandis.
`The invention will now be illustrated by the following
`examples.
`
`EXAMPLEI
`
`8
`continued
`
`
`
`
` mg per capsule
`
`350
`POE (40) hydrogI-ted castor oil
`(CREMOPHOR Rim)
`
`40
`Glyceryl Mono-cloak
`
`TOTAL 630
`
`The three ingredients were heated together with stirring.
`with the temperature being kept below 60° C. After cooling
`to below 40° C.. the mixture was filled into capsules. These
`temperatures are indicative, but not restrictive 0n storage at
`25° C.. the capsules were very strong and pliable after 3
`months. and the mix was clear and of one phase.
`EXAMPLE 2
`
`Capsules of 200 mg Evening Primrose Oil per capsule
`were prepared using the following proportions. in size “0"
`hard gelatin capsules:
`
`
` me nor camule
`
`Evening Primrose Oil
`POE (4-D) hydrogenated castor oil
`(CREMOPHOR RSI-140)
`POE (35] castor oil
`(CREMOPHOR EL)
`Glyceryl mono-cleatc
`Glych
`Water
`
`200
`210
`
`90
`
`TD
`15
`15
`
`
`
`TOT)“. 600
`
`The six ingredients were heated together with stirring.
`with the temperature being kept below 60° C. After cooling
`to below 40° C.. the mixture was filled into capsules. These
`temperatures are indicative. but not restrictive. On storage at
`25° C._. the capsules remained strong and very pliable. with
`the mix being clear.
`
`EXAMPLE 3
`
`10
`
`15
`
`20
`
`25
`
`35
`
`Capsules of 250 mg Evening Primrose Oil per capsule
`were prepared using the following proportions. in size “0“
`hard gelatin capsules:
`
`
`45
`
` me per capsule
`Evening Primrose Oil
`150
`POE [40) hydrogenated castor oil
`115
`(CREMGPHOR [11140)
`POE (35) ease: oil
`(CREMOPHOR EL)
`Glyceryl mooooieate
`Glycerol
`“later
`
`90
`rs
`15
`
`115
`
`55
`
`
`
`m 600
`
`Capsules of 200 mg Evening Primrose Oil per capsule
`were prepared using the following proportions. in size “0”
`hard gelatin capsules:
`
`
`mg per capsule
`Evening Primrose Oil
`2130
`
`65
`
`Page 5 of 8
`
`The six ingredients were heated together with stirring.
`with the temperature being kept below 60° C. After cooling
`to below 40" C.. the mixture was filled into capsules. These
`temperatures are indicative. but not restrictive. On storage at
`25° C.. the capsules remained strong and very pliable. with
`the mix being clear.
`
`EXAMPLE 4
`
`Capsules of 250 mg fish oil (EPAMARJNE—30% EPA
`+DHA) Were prepared in the same manner as Example 3.
`
`Page 5 of 8
`
`

`

`5,738,871
`
`9
`except that 250 mg of fish oil was used per capsule in place
`of th 250 mg of Evening Primrose Oil used in Example 3.
`The capsules were also very strong and very pliable on
`storage at 25° C., and the mix remained clear.
`EXAMPLES SA TO 5Q
`In order to exemplify the use of POE (40) hydrogenated
`caster oil (CREMOPHOR RH40) and POE (35) castor oil
`(CREMOPHOR EL) as solubilising agents for formulations
`for hard gelatin capsules. a number of natural oils were
`tested using either of the two surfactants alone with glyceryl
`mono-oleate. or as 50/50 mixtures of the two surfactants
`with glyceryl mouo-oleate. The basic composition tested
`was:
`
`
`ms
`
`Oi]
`' 250
`Surfactant
`200
`Glyoelyi morn-clean:
`120
`
`15
`water
`
`
`
`TOTAL 535
`
`10
`
`15
`
`20
`
`The results were as per the following table. with the coding:
`*=clear mixture, satisfactory solubilisation of the oil in
`water
`
`25
`
`H=hazy mixture
`2L=separation into 2 layers
`PS=poor solubilisation of the oil in water
`NT=not tested
`
`
`CRElA-‘IDEEOE TYPE
`mm
`
`(50:50)R340 EL
`
`Sweet Nit-10nd Oil
`Amelia Oil
`Btu-age Oil
`Blackcurrant Seed Oil
`Cod Liver Oil
`Cm Oil
`Cottonseed Oil
`Fish Oil (30% EPA + DHA)
`Grapeseed Oil
`Halibut Di}
`Linseed Oil
`Olive Oil
`Safllower 0‘s]
`Hybrid Safloumr Oil
`{high oleic acid]
`. Sam Oil
`P. Scyabenn Oil
`Q. Simllower Oil
`
`PS
`
`ESE:
`
`EFFPl.
`
`10
`gelatin capsules, the components being mixed together at a
`temperature between 40° and 50° C.:
`
`
`mg per capsule
`
`
`d-alpha-toeopheryl acetate
`(110?) Mg)
`POE (35) castor oil
`(CREMOPHOR EL)
`Glyceryl mono-oleate
`TOTAL
`
`211')
`
`205
`
`20
`425
`
`The temperature of mixing was approximately 50° C. The
`capsules were filled into hard gelatin capsules and sealed
`using the Licaps technique. The capsules were very strong
`and the contents were clear after storage for three months.
`
`EXAMPLES 7-12
`
`Capsule mixes of 200m vitamin E per capsule were
`prepared using the following proportions for size “1” hard
`gelatin capsules. the fill weight being 425 mg per capsule
`and the components being mixed at 40°40" (1.:
`
`
`Example
`
`No
`mg per capsule
`
`I?
`
`8
`
`9
`
`1|]
`
`ll
`
`12
`
`d—alpha-tooopheryl acetate
`([360 Mg)
`POE {35) caster oi] (CREMUPHOR EL}
`Glycerol
`Water
`TUIAL
`d-alpha-tocopberyl acetate
`(1360 tats)
`POE (35) caster oil (CREMDPHOR EL)
`Glyceryl morn-elem
`We
`TOTAL
`delpha-tocopheryl acetate
`(1100 iufg)
`POE (35) castor 051(CREMOPHOR EL)
`Glycerol
`Water
`mm
`d-alpha-tooopllery! acetate
`{1100 iutg)
`POE (35) castor oil (CREMOPHOR El.)
`Glyceryl mono-clean
`“am
`TOTAL
`dl-alpha-taooopheryl acetate
`(1000 Ms)
`PCB (35) caster oil (CREMOPEOR EL)
`Glycerol
`“w
`TOTAL
`dl—alpha-eowpheryl acetate
`(1000 iufg)
`POE [35) castor oil (CREMOPHOR EL)
`Glyceryl mono-elem:
`Water
`TOTAL
`
`EXAMPLE13
`
`30
`
`35
`
`45
`
`50
`
`.55
`
`55
`
`14?
`
`253
`10
`.12
`425
`14‘?
`
`248
`20
`A]
`415
`132'
`
`23
`10
`L0
`42.5
`132
`
`213
`20
`40
`415
`200
`
`205
`10
`.10.
`425
`2.03
`
`195
`20
`fl‘
`425
`
`0zFrneuasmePoee
`
`naaephumecaaee
`
`Illluulmilllll
`
`:53!
`
`
`
`we;figfilfiaaeifiaafiu E
`
`o T
`
`temperatures
`
`he components were mixed together at
`between 40 and 50° C.
`From the above. it is clear that each oil can be subjected
`to simple testing to determine the most suitable surfactant.
`or combination of surfactants. Glyceryl mono—oleate is very
`beneficial in enhancing solubilisation. If necessary, small.
`amounts of glycerol can be added to any of the above
`formulations to improve pliability if required. The use of
`glyceryl monooleate at the level of this example is for
`illustrative purposes only. It may be used at difierent levels
`depending on the ease or difficulty in achieving a suitable
`mix in teams of clarity and solubilising capability.
`EXAMPLEfi
`
`Capsule mixes of 200 in Vitamin-E per capsule were
`prepared using the following proportions. for size “1” hard
`
`Capsules of 50.000 iu vitamin A per capsule were pre-
`pared using the following proportions in. size “2" hard
`
`Page 6 of 8
`
`Page 6 of 8
`
`

`

`5,738,871
`
`12
`
`
`
`
` mg per capsule
`
`100
`464] g
`d—alpha-tocephmol (EDD iulg)
`315
`1448 g
`POE [35) castor oil (CREMOPHOR EL.)
`10
`46 g
`Glycerol
`
`
`46 gPurified water 10
`
`ID
`
`15
`
`The mix was prepared by mixing and heating to approxi-
`mately 50° C. The mix was encapsulated in size “1"
`LICAPS hard gelatin capsules with gelatin banding. After
`three months, the formulation was found to be stable in
`terms of vitamin B activity. and the capsules were very
`strong with adequate pliability after this storage time.
`EXAMPIE 1'?
`
`A batch of capsules containing 100 in vitamin E and 10
`mg beta-carotene per capsule was prepared for size “ 1” hard
`gelatin capsules. using the following formulation:
`
`
` mg per capsule
`
`11
`
`gelatin capsules:
`
`
`
`
` ma per capsule
`
`Vitamin A palmitate
`(1.1 m.i.I.Lig)
`POE (40) hydrogenated castor oil
`(CREMOPHOR kit-10)
`Glycerol
`Water
`
`30
`
`175
`
`12.5
`
`12.5
`
`
`
`TO'L'AL 315
`
`The mixing of the components was at 40~50° C.
`Alternatively. P013 (35) caster oil (CREMOPHOR EL) can
`be used as the surfactant.
`
`EXAMPLE 14
`
`Capsules of 400m vitamin D per capsule. i.e. 10 micro-
`gram cholecalciferel pa capsules. were prepared using the
`following proportions in size “2“ hard gelatin capsules:
`
`
`
`
` mg per capsule
`
`Wtamin D (Cholccalciferol)
`PCB (40) hydrogenated caster oil
`(CREMOPHOR RHIt-O)
`Glycerol
`Water
`
`0.01
`290
`
`12.5
`
`12.5
`
`
`
`TOTAL 315.01
`
`till—50° C.
`The mixing of components was at
`Alternatively. POE (35} castor oil (CREMOPHOR EL) can
`be used as the surfactant.
`
`EXAMPLE 15
`
`Capsules of 1 mg vitamin K per capsule, present as
`vitamin K or phylemenadione. were prepared using the
`following proportions in size “2” hard gelatin capsules:
`
`
`Vitamin K
`POE (40) hydrogenated caster oil
`{CREMOPHOR RIM-0)
`Glycerol
`Water
`
`ms per capsule
`1
`290
`
`12
`
`12
`
`
`
`TOTAL 315
`
`The mixing of components was at 410—50" C.
`Alternatively, POE (35) caster oil (CREMOPHOR EL) can
`be used as the surfactant.
`
`Note that combinations of vitamins E. A. audior D can be
`achieved through sensible combinations of the formulations
`from the above examples.
`
`EXAMPLE 16
`
`A batch of capsules containing 100m vitamin E per
`capsule was prepared. for size “1” hard gelatin capsules.
`using the following formulation:
`
`Page 7 of 8
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`dralphamocopheml (1000 mtg)
`Beta—carotene
`[30% fluid suspension in
`Arachis Oil)
`POE (35) castm all
`(CREMOPHDR EL]
`10.0
`46 g
`Glycerol
`
`
`46 gPurified water 10.0
`
`4-60 3
`154 g
`
`1294 5
`
`100.1
`33.5
`
`281.4
`
`The mix was prepared by mixing and heating to approxi-
`mately 50" C. The mix was encapsulated in size "1"
`LICAPS hard gelatin capsules with gelatin banding. After
`three months the formulation was found to be stable in terms
`